Currently, there is no preventative treatment for age-related macular degeneration (AMD), the leading cause of blindness among the elderly in the U.S.. Development of therapeutic interventions will require an understanding of the molecular events associated with the disease. In this proposal, we will test the hypothesis that a subset of proteins will be uniquely altered with AMD and that the progression of AMD will involve an evolution of protein changes that are manifest in clinically distinct features. This research will take an innovative analytical approach by using proteomic technology to identify specific proteins that are altered in the sensory retina and retinal pigment epithelium (RPE) with AMD. Donors selected (ages 65-75) will include those exhibiting either no AMD (control) or retinal features that are indicative of the beginning or later stages of the disease. The following aims will be pursued: (1) Evaluate and classify retinal degeneration in donor eyes. Prior to biochemical analysis, we will evaluate the macular region of donor eyes using the Age-related Eye Disease (AREDS) system. (2) Identify alterations in retinal proteins using proteomic analysis. We will perform proteome analysis to identify proteins in the RPE and sensory retina that have altered expression or contain the oxidative modification, 4-hydroxynonenal. Using donor retinas at clinically defined stages of AMD should aid in distinguishing patterns of protein changes that are associated with the progression of the disease. Identification of proteins that are uniquely altered will help provide valuable insight into the mechanism of AMD.